DNA repair is required by organisms to prevent the accumulation of mutations and to maintain the integrity of genetic information. Compromise of genetic information may result in dysregulation of cellular growth control, and ultimately tumor formation. Nucleotide excision repair (NER) removes a broad spectrum of DNA mutations, including ultraviolet light-induced photo-products, bulky chemical adducts, intrastrand cross-links, and interstrand cross-links (Weeda et al, BioEssays, 15:249 (1993)).
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease. Cells cultured from XP patients have an increased sensitivity to ultraviolet light (UV), and a phenotype related to defective NER (Cleaver, Nature, 218:652 (1968)). This disease is characterized primarily by hypersensitivity of the skin to sunlight, with cutaneous symptoms that may include pigmentation abnormalities, and a greater than 1000-fold increased risk of skin cancers in sun-exposed parts of the body (Cleaver, In: The Metabolic Basis of Inherited Disease, McGraw Hill, New York (1995)). XP is a heterogenous disease, with some patients exhibiting progressive neurologic degeneration, as well as sensitivity to sunlight. Cell fusion complementation studies have revealed eight complementation groups in XP (A-G, and an XP-variant form) (Cleaver, supra).
XP group C (XPC) is one of the most common forms of the disease, and is characterized by an NER defect in transcription-independent repair, with apparently normal rates of repair of the transcribed strand of active genes (Venema et al, Mol. Cell. Biol., 11:4128 (1991)). In rodents afflicted with XPC, the large untranscribed regions of the genome remain unrepaired, while small actively transcribed regions are repaired (Bohr, Carcinogenesis, 12:1983 (1991)).
The human xpc gene has been cloned by complementation of the NER defect, and found to contain a region of homology to the yeast RAD4 gene (Legerski et al, Nature, 359:70 (1992)). The human xpc gene has been found to be mutated in cell lines from XPC patients (Li et al, Nature Genetics, 5:413 (1993)). Thus, the cloning of the human xpc gene has allowed for genetic screening of XPC in humans. However, heretofore, there has been no animal model for XPC to allow for screening for the damaging and tumorigenic effect of ultraviolet light and chemical DNA damaging agents. The present invention has provided for the first time such an animal model for XPC.